Resveratrol alleviates depression-like behaviors by inhibiting ferroptosis via AKT/NRF2 pathway

Major depressive disorder (MDD) is common, and successful treatment remains challenging. Resveratrol, a naturally occurring polyphenol, has been shown to alleviate depression-like behaviors, but the underlying mechanisms remain unclear. We previously developed a new model of depression by inducing hippocampal ferroptosis in rats, suggesting that ferroptosis may be involved in the development of MDD. Here, we further explored the antidepressant-like effect of resveratrol and its association with ferroptosis. Male rats were exposed to chronic unpredictable mild stress (CUMS), with or without resveratrol, followed by comprehensive behavioral testing. In PC12 cells in vitro, LY294002 (an AKT inhibitor) and ML385 (an NRF2 inhibitor) were used to elucidate the involvement of AKT/NRF2 signaling in resveratrol-mediated ferroptosis. mRNA and protein levels of AKT/NRF2 pathway and ferroptosis-related targets were measured. Ferroptosis was quantified by measuring malondialdehyde (MDA), glutathione (GSH), and Fe²⁺ content and superoxide dismutase (SOD) activity. Resveratrol ameliorated depression-like behaviors in rats, simultaneously restoring AKT/NRF2 pathway and ferroptosis-related targets in the hippocampus downregulated by CUMS. Elevated markers of oxidative stress in plasma were attenuated by resveratrol. Furthermore, erastin induced ferroptosis and inhibited AKT/NRF2 signaling in PC12 cells, which was counteracted by resveratrol. Additionally, the impact of resveratrol on erastin-induced ferroptosis was reversed by LY294002 and ML385. This study demonstrates that resveratrol ameliorates depression-like behaviors by inhibiting ferroptosis via the AKT/NRF2 pathway.